Chemical Mechanism of the Covalent Modification of 5-Alpha-Reductases by Finasteride as Probed by Secondary Tritium Isotope Effects

    March 1995 in “ Journal of the American Chemical Society ”
    Gaochao Tian, Shiang-Yuan Chen, Kevin L. Facchine, Shimoga R. Prakash
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    TLDR Finasteride modifies 5-alpha-reductases through a two-step process, affecting inhibitor potency and possibly causing side effects.
    This study examines the chemical mechanism of the covalent modification of 5-alpha-reductases by finasteride. The study suggests a two-step mechanism involving a high barrier addition of the attacking nucleophile at C-1, followed by a low barrier protonation at C-2. The proposed mechanism has implications for the design of novel covalent inhibitors for use as pharmaceutics. The study also notes that the partitioning of the activated intermediate, which occurs in the mechanism-based inhibition, undermines the potency of the inhibitor and possibly causes adverse effects in vivo.
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